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Activation of a TGF-β-Specific Multistep Gene Expression Program in Mature Macrophages Requires Glucocorticoid-Mediated Surface Expression of TGF-β Receptor II¹

Alexei Gratchev^2,3,*, Julia Kzhyshkowska^2,*, Sheila Kannookadan^*, Miriam Ochsenreiter^*, Anna Popova^*, Xiaolei Yu, Srinivas Mamidi^*, Eugenia Stonehouse-Usselmann^*, Isabelle Muller-Molinet^*, LiMing Gooi^* and Sergij Goerdt^*

^* Department of Dermatology and Medical Research Center, Medical Faculty Mannheim, Ruprecht-Karls University of Heidelberg, Mannheim, Germany

Alternatively activated (M2) macrophages regulate steady state-, cancer-, and inflammation-related tissue remodeling. They are induced by Th2-cytokines and glucocorticoids (GC). The responsiveness of mature macrophages to TGF-β, a cytokine involved in inflammation, cancer, and atherosclerosis, is currently controversial. Recently, we demonstrated that IL-17 receptor B is up-regulated in human monocyte-derived macrophages differentiated in the presence of Th2 cytokines IL-4 and TGF-β1. In this study, we show that mature human macrophages differentiated in the presence of IL-4, and dexamethasone (M2_IL-4/GC) but not M2_IL-4 responds to TGF-β1 which induced a gene expression program comprising 111 genes including transcriptional/signaling regulators (ID3 and RGS1), immune modulators (ALOX5AP and IL-17 receptor B) and atherosclerosis-related genes (ALOX5AP, ORL1, APOC1, APOC2, and APOE). Analysis of molecular mechanism underlying GC/TGF-β cooperation revealed that surface expression of TGF-βRII was high in M2_GC and M2_IL-4/GC, but absent from M2_IL-4, whereas the expression of TGF-βRI/II mRNA, TGF-βRII total protein, and surface expression of TGF-βRIII were unchanged. GC dexamethasone was essential for increased surface expression of functional TGF-βRII because its effect was observed also in combination with IL-13, M-CSF, and GM-CSF. Prolonged Smad2-mediated signaling observed in TGF-β1-treated M2_IL-4/GC was due to insufficient activity of negative feedback mechanism what can be explained by up-regulation of SIRT1, a negative regulator of Smad7, and the retention of TGF-βRII complex on the cell surface. In summary, mature human M2 macrophages made permissive to TGF-β by GC-induced surface expression of TGF-βRII activate in response to TGF-β1, a multistep gene expression program featuring traits of macrophages found within an atherosclerotic lesion.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Deutsche Forschungsgemeinschaft SFB405, Project B12 (to S.G. and J.K.), and the Margarete von Wrangell Habilitationsprogramm (to J.K.).

² A.G. and J.K. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Alexei Gratchev, Klinik für Dermatologie, Venerologie und Allergologie, Klinikum Mannheim gGmbH-Universitätsklinikum, Ruprecht-Karls-Universität Heidelberg, Theodor-Kutzer-Ufer 1–3, 68167 Mannheim, Germany. E-mail addresses: alexei.gratchev{at}haut.ma.uni-heidelberg.de and alexei.gratchev{at}gmail.com

⁴ Abbreviations used in this paper: GC, glucocorticoid; IL17RB, IL-17 receptor B; R-Smad, receptor-regulated Smad; FC, fold change.